2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine is the compound represented by the following Formula (1):
(hereinafter referred to as Compound (1) or TKD), which is one of nucleoside analogue reverse transcriptase inhibitors (NRTIs). Compound (1) is a medicinal compound useful as a drug for preventing the development of the acquired immunodeficiency syndrome, and is known to have an activity superior to that of the commercially available similar drug Stavudine (2′,3′-didehydro-3′-deoxythymidine, d4T).
As the process for synthesizing Compound (1), the following three main types have been reported so far. However, while the 1st and the 2nd synthetic processes produce optically pure Compound (1), the 3rd process produces a racemate. Therefore, only two kinds of processes substantially exist.
The scheme of the 1st synthetic process, which was the first reported route, is as shown below. Thymidine as a starting material is converted into a 4′,5′-unsaturated derivative. Next, a 4′,5′-epoxy compound or a 4′,5′-bisacyloxy compound is synthesized. Then, an organoaluminum compound having an ethynyl group is reacted with the synthesized compound to give an adduct, and further a 2′,3′-unsaturated bond is introduced to give Compound (1) (non patent literatures 1, 2, and 3, and patent literatures 1 and 2).
(In the scheme, Ph represents a phenyl group, Et represents an ethyl group, and TBDMS represents a tert-butyldimethylsilyl group.)
The 2nd route is as shown below. Similarly, thymidine is used as a starting material. By replacement of a bulky protecting group, such as a dimethoxytrityl group (DMT group), a tert-butyldimethylsilyl group (TBS or TBDMS group), tert-butyldiphenylsilyl group (TBDPS group), or the like, a hydroxymethyl group is introduced into position 4′ and selective protection of the hydroxy group at position 5′ is performed. Then, the hydroxymethyl group at position 4′ is oxidized into a formyl group and subsequently converted into a chloro ethenyl group by the Wittig reaction. Then, butyl lithium (BuLi) is used to convert the chloro ethenyl group into an ethynyl group. Thus, an ethynyl group is stereoselectively introduced into position 4′. Finally a 2′,3′-unsaturated bond is introduced to give Compound (1) (patent literatures 1 and 2).
(In the scheme, each symbol has the same meaning as defined in the patent literatures 1 and 2.)
The 3rd route is as shown below. Isopropyl acetate as a starting material is converted into a ketoester through several steps. The ketoester is reacted with ethynylmagnesium bromide and thereby converted into propargyl alcohol. The reduction of the ester group to an aldehyde and subsequent lactol ring formation give a furanose derivative. The furanose derivative is condensed with silylated thymine to give a nucleoside (a 1:1 mixture of α- and (β-anomers). After the objective β-anomer is separated, finally a 2′,3′-unsaturated bond is introduced to give a racemate [I] (non patent literature 4).
(In the scheme, TBDMS represents a tert-butyldimethylsilyl group, TMS represents a trimethylsilyl group, OTf represents a trifluoromethane sulfonyloxy group, MOM represents a methoxymethyl group, and Ac represents an acetyl group.)
However, the above processes have various problems: since the raw material is expensive, industrial production is difficult due to the high cost; a significant amount of a hazardous or toxic compound or the like is used; and separation or purification of an intermediate having a silyl group as a protective group is difficult because such an intermediate is hard to crystallize.